Blood cells are comprised of diverse and distinctive cell types derived from a common progenitor stem cell in the bone marrow. Blood cells are classified as either red or white. Red blood cells, or erythrocytes, transport oxygen through the bloodstream. White blood cells, or leukocytes, are involved in various aspects of the immune response, including inflammation and defense against infection. Leukocytes are further classified into three major cell types: lymphocytes, granulocytes, and monocytes. Lymphocytes include T- and B-cells, which specifically recognize and respond to foreign pathogens. T-cells are important for fighting viral infections and activating other leukocytes, while B-cells secrete antibodies that neutralize bacteria and other microbes. Granulocytes and monocytes are primarily migratory, phagocytic cells that exit the bloodstream to fight infection in tissues. Monocytes, which are derived from immature promonocytes, further differentiate into macrophages that engulf and digest microorganisms and damaged or dead cells. Granulocytes, which include neutrophils, basophils, eosinophils, and mast cells, are also important in phagocytosis and in the allergic response. Dendritic cells are a rare type of leukocyte which resides in lymphoid organs, such as the thymus, and in specialized cells of the skin called Langerhans cells. Dendritic cells are characterized by unusual pseudopodial and elongated processes extending from the cell surface. Dendritic cells are antigen-presenting cells that play a key role in T-cell activation.
Monocytes and macrophages modulate the immune response by secreting signaling molecules such as growth factors and cytokines. Tumor necrosis factor-.alpha. (TNF-.alpha.), for example, is a macrophage-secreted protein with anti-tumor and anti-viral activity. In cultured monocytes, TNF-.alpha. expression is stimulated by phorbol ester, a class of compounds which artificially trigger signal transduction. A messenger RNA (mRNA) transcript: related to a monocyte mRNA transcript involved in phorbol ester-induced expression of TNF-.alpha. has been isolated from estrogen-treated rat uterus. This transcript, estrogen enhanced transcript-1 (EET-1: GI 1279978; SEQ ID NO:3), contains an open reading frame that encodes a 161 amino acid protein (EET-1 ORF). EET-1 ORF contains several potential phosphorylation sites and a C-terminal cysteine rich region, suggesting that this protein is involved in gene regulation and signal transduction. (Everett, L. M. et al. (1997) Endocrinology 138:3836-3841.)
In addition, monocytes and macrophages are recruited to sites of infection and inflammation by signaling proteins secreted by other leukocytes. For example, numerous related low molecular weight cytokines, called chemokines, have been identified as leukocytic secretory products with chemoattractant activity. Chemokines play a key role in inflammatory and infectious diseases such as acquired immunodeficiency syndrome (AIDS). Chemokines are classified as C, CC, CXC, and CX.sub.3 C, based on the number and position of critical cysteine residues. (Bazan, J. F. et al. (1997) Nature 385:640-644; Wells, T. N. and Peitsch, M. C. (1997) J. Leukoc. Biol. 61:545-550.)
The differentiation of the monocyte blood cell lineage can be studied in vitro using cultured cell lines. For example, THP-1 is a human promonocyte cell line that can be activated by treatment with both phorbol ester, such as phorbol myristate acetate (PMA), and lipopolysaccharide (LPS). These reagents mimic the signals that trigger promonocyte and monocyte differentiation in vivo. In addition, treatment with nucleotide analogs, such as 5-aza-2'-deoxycytidine (5AZA), promotes cell differentiation by activating gene transcription.
The discovery of a new promonocyte associated protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of immune, cell proliferative and reproductive disorders, and infections.